Copper-catalyzed decarboxylative coupling reactions for the synthesis of propargyl amines

Accepted Manuscript Copper-Catalyzed Decarboxylative Coupling Reactions for the Synthesis of Propargyl Amines Jeongah Lim, Kyungho Park, Aleum Byeun, Sunwoo Lee PII: DOI: Reference:

S0040-4039(14)01110-1 http://dx.doi.org/10.1016/j.tetlet.2014.05.134 TETL 44822

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

13 April 2014 25 May 2014 27 May 2014

Please cite this article as: Lim, J., Park, K., Byeun, A., Lee, S., Copper-Catalyzed Decarboxylative Coupling Reactions for the Synthesis of Propargyl Amines, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet. 2014.05.134

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Copper-Catalyzed Decarboxylative Coupling Reactions for the Synthesis of Propargyl Amines Jeongah Lim, Kyungho Park, Aleum Byeun, and Sunwoo Lee*

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Copper-Catalyzed Decarboxylative Coupling Reactions for the Synthesis of Propargyl Amines Jeongah Lim a, Kyungho Park a, Aleum Byeun a, and Sunwoo Lee a a

Department of Chemistry, Chonnam National University, Gwangju, 500-757, Republic of Korea

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

When aryl alkynyl carboxylic acids were allowed to react with amines and aldehydes in CH3CN at 80 oC in the presence of 10 mol% CuI, the desired propargyl amines were formed in good yields. This coupling reaction demonstrated to work across a broad range of reagents including functionalized aryl alkynyl carboxylic acids, aliphatic and aromatic aldehydes and cyclic and acyclic amines

Keywords: Decarboxylative coupling Alkynyl carboxylic acid Copper A3 coupling Propargyl amine

2014 Elsevier Ltd. All rights reserved.

The multicomponent coupling reactions provide an elegant means for molecular synthesis because of their simple, efficient one-step processes.1 Among them, A3 coupling, the coupling reaction of an alkyne, aldehyde and amine that we are utilizing in the synthesis of propargyl amines, has attracted attention due to the fact that propargyl amines are widely employed as key intermediates in the construction of biologically active compounds.2 Propargyl amines have also been prepared through classical methods such as the nucleophilic attack of metal acetylides on the imines or their derivatives.3 However, these methods are moisture-sensitive and produce large quantities of metal waste. Compared with such classical methods, A3 coupling has several advantages, including the possibility of transitionmetal catalysis and the generation of waster as an environmentally friendly byproduct. A number of homogeneous transition metals such as gold,4 silver,5 iridium,6 and copper7 have been used and proven effective in A3 coupling reactions. Additionally, reusable heterogeneous metal catalysts and continuous flow reaction systems were also developed for the synthesis of propargyl amines.8 However, all of these methods employed terminal alkynes as alkyne sources. Furthermore, in the case where aryl group bonded to terminal alkynes, a multistep process was necessary. In place of terminal aryl alkynes, aryl alkynyl carboxylic acids offer several advantages as alkynyl source: their stability facilitates handling and storage, and they are easily prepared through a simple process. 9 Since our first report in 2008,10 many decarboxylative coupling reactions have been developed using transition metals such as palladium,11 copper,12 nickel,13 and silver.14 Additionally, alkynyl carboxylic

———

 Corresponding author. Tel: +82-62-530-3385, Fax:+82-62-530-3389 E-mail address : [email protected] (S.Lee).

acids have been utilized multicomponent reactions.15

as

alkyne

sources

in

other

Recently, we reported a metal-free synthesis of propargyl amines via the decarboxylative coupling of aryl alkynyl carboxylic acids with formaldehyde and amines.16 Although this method provided an environmentally friendly protocol for the construction of propargyl amines in aqueous conditions without the need for a metal catalyst, formaldehyde was the only aldehyde source which produced a good yield. To expand the decarboxylative coupling reaction for the synthesis of propargyl amines to the broad ranges of aldehydes, we employed copper catalyst in the coupling reaction of alkynyl carboxylic acids, amines and aldehydes. Here, we report the copper-catalyzed decarboxylative coupling reaction of aryl alkynyl carboxylic acid with aldehydes and amines for the synthesis of propargyl amines. To find optimal conditions, we chose phenyl propiolic acid, benzaldehyde and morpholine as standard substrates. When the reaction was conducted in the absence of catalyst, no product was formed (entry 1). The use of copper(II) complexes such as Cu(OAc)2 and Cu(OTf)2 yielded the desired product in 82% and 72%, respectively (entries 2 and 3). Copper(I) complexes such as CuCl and CuI also produced the propargyl amine product with 55% and 92% yields, respectively (entries 4 and 5). With CuI as a catalyst, a variety of solvents were tested, and most cases provided the desired coupled product in moderate to good yields (entries 5–13). Among them, CH3CN was found to be the best solvent (entry 5). Decreasing the reaction temperature to 60 oC and 25 oC, reduced the product yield of product to 42% and 12%,

2

Tetrahedron

respectively (entries 14 and 15). Based on these results, we found that 10 mol% CuI showed the best activity in CH3CN at 80 o C.

Table 2. Copper-catalyzed decarboxylation for the synthesis of propargyl amines.a

Table 1. The optimization condition for the synthesis of propargyl amines.a

Entry

Catalyst

Solvent

Temp (oC)

Yield (%)

1

No catalyst

CH3CN

80

-

2

Cu(OAc)2

CH3CN

80

82

3

Cu(OTf)2

CH3CN

80

72

4

CuCl

CH3CN

80

55

5

CuI

CH3CN

80

92

6

CuI

Toluene

80

72

7

CuI

Dioxane

80

73

8

CuI

diglyme

80

56

9

CuI

EtOH

80

82

10

CuI

MeOH

80

54

11

CuI

DMSO

80

87

12

CuI

DMF

80

47

13

CuI

NMP

80

64

14

CuI

CH3CN

60

42

15

CuI

CH3CN

25

12

16

CuI 5%

CH3CN

80

83

17

CuI 1%

CH3CN

80

38

a

Reaction conditions : 1a (0.3 mmol), 2a (0.3 mmol), 3a (0.3 mmol) and catalyst (0.03 mmol) were reacted in solvent (1.0 mL). bDetermined by gas chromatography with internal standard. cCuI (0.015 mmol) was used. dCuI (0.03 mmol) was used.

To evaluate the scope of the A3 coupling reactions, we tested a variety of combination of aldehydes, amines and aryl alkynyl carboxylic acids.17 When phenyl propiolic acid and benzaldehyde were allowed to react with a variety of cyclic and acyclic amines, the desired propargyl amines were formed. Cyclic amines such as morpholine, piepridine and pyrrolidine produced the corresponding propargyl amines 4a, 4b and 4c with 92%, 89% and 94% yields, respectively (entries 1 - 3). The coupling yields from the acyclic amines such as N-methylphenylamine and diallylamine were a bit lower than those for the cyclic amines (entries 4 and 5) and these results imply that this particular coupling reaction might be sensitive to the steric environment of the substrates. Coupling reactions of 4-tert-butylbenzaldehyde or halo-substituted benzaldehydes with phenyl propioloic acid and morpholine provided the desired products in good yields (entries 6–9). When phenyl propiolic acid and 6-methoxy-2naphthaldehyde were allowed to react with cyclic amines, the desired products 4j, 4k and 4l were formed in 73%, 79% and 81% yields, respectively (entries 10–12). Hexanal afforded the desired products with good yields in the coupling reaction of phenyl propiolic acid and cyclic amines (entries 13–15). Methyl or methoxy substituted phenyl propiolic acid produced the corresponding propargyl amines with excellent yields (entries 16 - 18). Additionaly, cyano- and ester- functionalized phenyl propiolic acids also afforded the corresponding propargyl amines with 49% and 56% yields, respectively (entries 19 and 20).

a

Reaction conditions : 1a (3.0 mmol), 2a (3.0 mmol), 3a (3.0 mmol) and catalyst (0.3 mmol) were reacted in CH3CN (10 mL) at 80 oC.

When phenyl propiolic aicd, paraformaldehyde and morpholine were allowed to react in the presence of copper catalyst, the desired product was formed with 97% yield (Our previous report showed that its yield was 98% in the absence of copper).16 We proposed the reaction mechanism as shown in Scheme 1. Aryl alkynyl carboxylic acid reacted with copper(I) catalyst to produce the alkynyl copper complex through decarboxylation (step i). The alkynyl copper complex then reacts with the imine formed in a reaction with aldehyde and amine to provide the desired propargyl amine (step ii). We suggest that copper catalyst may accelerate the decarboxylation step and increase the nucleophilicity of alkyne to attack the imine because no product form in the absence of copper.

Scheme 1. Proposed Mechanism

3 In summary, we have developed copper-catalyzed three component reactions for the synthesis of a number of different propargyl amines from different aryl alkynyl carboxylic acids, aldehydes and amines combinations. When 10 mol% CuI was employed as a catalyst in CH3CN at 80 oC, high yields of desired propargyl amines were obtained. This reaction method applied across a broad scope of substrates including functionalized aryl alkynyl carboxylic acids, cyclic and acylic amines, and aromatic and aliphatic aldehydes.

Acknowledgement This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant number 2012R1A1B3000871). Spectra data were obtained from the Korea Basic Science Institute, Gwangju branch. References and notes 1.

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Chem. 2012, 5038–5047; c) Feng, H.; Ermolat’ev, D. S.; Song, G.; Van der Eychen, E. V. J. Org. Chem. 2012, 77, 5149–5154; e) Kumar, M. R.; Irudayanatham F. M.; Moon, J. H.; Lee, S. Adv. Synth. Catal. 2013, 355, 3221–3230; f) Palani, T.; Park, K.; Song, K. H.; Lee, S. Adv. Synth. Catal. 2013, 355, 1160–1168. 16. Park, K.; Heo, Y.; Lee, S. Org. Lett. 2013, 15, 3322–3325 17. Typical experimental procedure: CuI (57.1 mg, 0.3 mmol), alkynyl carboxylic acid (3.0 mmol) aldehyde (3.0 mmol) and amine (3.0 mmol) were combined with acetonitrile (10 mL) in a small round-bottomed flask. The mixture was stirred at 80 oC until the reaction completed. The reaction mixture was poured into water and extracted with EtOAc. The solvent was removed under vacuum, and the resulting crude product was purified by flash chromatography on silica gel to give the desired product. 4-(1,3-Diphenylprop-2-ynyl)morpholine (4a): 1H NMR (300 MHz, CDCl3) δ 7.70–7.58 (m, 2H), 7.57–7.44 (m, 2H), 7.43–7.15 (m, 6H), 4.78 (s, 1H), 3.84–3.60 (m, 4H), 2.63 (t, J = 4.1 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 162.82, 140.58, 131.79, 129.60, 128.39, 128.32, 124.06, 122.65, 115.39, 114.66, 88.81, 84.17, 67.09, 61.49, 49.79. 1-(1,3-Diphenylprop-2-ynyl)piperidine (4b): 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J = 7.9, 1.1 Hz, 2H), 7.57–7.45 (m, 2H), 7.41–7.24 (m, 6H), 4.79 (s, 1H), 2.56 (t, J = 5.3 Hz, 4H), 1.59 (dd, J = 10.7, 5.2 Hz, 4H), 1.44 (dd, J = 11.2, 5.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 138.59, 131.76, 128.46, 128.22, 128.00(2C), 127.38, 123.30, 87.77, 86.05, 62.34, 50.65, 26.16, 24.41. 1-(1,3-Diphenylprop-2-ynyl)pyrrolidine (4c): 1H NMR (300 MHz, CDCl3) δ 7.67–7.56 (m, 2H), 7.56–7.42 (m, 2H), 7.41–7.24 (m, 6H), 4.87 (s, 1H), 2.78–2.57 (m, 4H), 1.91–1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 139.49, 131.72, 128.20(3C), 128.01, 127.49, 123.18, 86.81, 86.67, 59.07, 50.22, 23.43. N-Benzyl-N-methyl-1,3-diphenylprop-2-yn-1-amine (4d): 1H NMR (300 MHz, CDCl3) δ 7.68 (m, 2H), 7.61–7.50 (m, 2H), 7.46–7.19 (m, 11H), 4.92 (s, 1H), 3.73 (d, J = 13.1 Hz, 1H), 3.64 (d, J = 13.1 Hz, 1H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.24, 139.00, 131.86, 128.98, 128.32(2C), 128.27, 128.15, 128.10, 127.48, 127.04, 123.22, 88.63, 84.66, 59.52, 58.88, 37.99. N-Allyl-N-(1,3-diphenylprop-2-ynyl)prop-2-en-1-amine (4e): 1H NMR (300 MHz, CDCl3) δ 7.78–7.62 (m, 2H), 7.59–7.53 (m, 1H), 7.53–7.48 (m, 1H), 7.40–7.22 (m, 6H), 6.02–5.66 (m, 2H), 5.36–5.23 (m, 2H), 5.17–5.10 (m, 2H), 5.10 (s, 1H), 3.34–3.15 (m, 2H), 3.05 (dd, J = 14.1, 8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 139.27, 136.45, 131.79, 128.27, 128.21, 128.08, 128.05, 127.35, 123.24, 117.29, 87.86, 85.31, 56.51, 53.51. 4-(1-(4-Tert-butylphenyl)-3-phenylprop-2-ynyl)morpholine (4f): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 8.1 Hz, 2H), 7.52–7.48 (m, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.33–7.27 (m, 3H), 4.75 (s, 1H), 3.83–3.56 (m, 4H), 2.81–2.49 (m, 4H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.60, 134.63, 131.71, 128.20(2C), 128.09, 125.05, 123.00, 88.12, 85.33, 67.10, 61.67, 49.81, 34.44, 31.31. 4-(1-(3-Fluorophenyl)-3-phenylprop-2-ynyl)morpholine (4g): 1H NMR (300 MHz, CDCl3) δ 7.63–7.47 (m, 2H), 7.47–7.41 (m, 1H), 7.41–7.27

4

Tetrahedron (m, 5H), 7.00 (t, J = 8.5 Hz, 1H), 4.79 (s, 1H), 3.87–3.60 (m, 4H), 2.63 (t, J = 4.6 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 162.81 (d, J = 245.6 Hz), 140.58 (d, J = 7.0 Hz), 129.60 (d, J = 8.1 Hz), 124.04 (d, J = 2.8 Hz), 115.39 (d, J = 22.5 Hz), 114.66 (d, J = 21.2 Hz); HRMS (ESI, TOF) calcd. for C19H19FNO [M+H]+ 296.1451, found 296.1454. 4-(1-(4-Chlorophenyl)-3-phenylprop-2-ynyl)morpholine (4h): 1H NMR (300 MHz, CDCl3) δ 7.68–7.53 (m, 2H), 7.53–7.43 (m, 2H), 7.38–7.22 (m, 5H), 4.73 (s, 1H), 3.70 (dd, J = 8.7, 4.1 Hz, 4H), 2.59 (t, J = 4.6 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 136.35, 133.39, 131.67, 129.73, 128.26, 128.22, 122.58, 88.78, 84.24, 66.95, 61.20, 49.63. 4-(1-(4-Bromophenyl)-3-phenylprop-2-ynyl)morpholine (4i): 1H NMR (300 MHz, CDCl3) δ 7.63–7.40 (m, 6H), 7.34– 7.32 (m, 3H), 4.73 (s, 1H), 3.74– 3.70 (m, 4H), 2.60 (t, J = 4.6 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 136.96, 131.75, 131.28, 130.18, 128.36, 128.30, 122.64, 121.68, 88.88, 84.21, 67.06, 61.37, 49.74. 4-(1-(6-Methoxynaphthalen-2-yl)-3-phenylprop-2-ynyl)morpholine (4j): 1 H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.81–7.62 (m, 3H), 7.61– 7.46 (m, 2H), 7.41–7.27 (m, 3H), 7.21–7.02 (m, 2H), 4.89 (s, 1H), 3.90 (s, 3H), 3.82–3.47 (m, 4H), 2.66 (t, J = 3.5 Hz, 4H).; 13C NMR (75 MHz, CDCl3) δ 157.80, 134.15, 133.00, 131.79, 129.52, 128.44, 128.28, 128.21, 127.28, 127.00, 126.79, 122.97, 118.81, 105.58, 88.57, 85.15, 67.12, 62.05, 55.25, 49.92. 1-(1-(6-Methoxynaphthalen-2-yl)-3-phenylprop-2-ynyl)piperidine (4k): 1 H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 1.2 Hz, 2H), 7.59–7.50 (m, 2H), 7.37–7.24 (m, 3H), 7.18– 7.08 (m, 2H), 4.89 (d, J = 0.8 Hz, 1H), 3.86 (s, 3H), 2.59 (t, J = 5.2 Hz, 4H), 1.58 (dd, J = 10.8, 5.3 Hz, 4H), 1.44 (dd, J = 11.0, 5.3 Hz, 2H).; 13 C NMR (75 MHz, CDCl3) δ 157.60, 133.98, 133.81, 131.74, 129.47, 128.43, 128.20, 127.96, 127.12, 127.02, 126.52, 123.29, 118.61, 105.49, 87.93, 86.13, 62.34, 55.13, 50.67, 26.11, 24.39; HRMS (ESI, TOF) calcd. for C25H26NO [M+H]+ 356.2014, found 356.2010. 1-(1-(6-Methoxynaphthalen-2-yl)-3-phenylprop-2-ynyl)pyrrolidine (4l): 1 H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.72 (m, 3H), 7.57–7.45 (m, 2H), 7.39–7.29 (m, 3H), 7.14 (m, 2H), 4.99 (s, 1H), 3.91 (s, 3H), 2.72 (t, J = 6.7 Hz, 4H), 1.81 (t, J = 6.3 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 157.69, 134.79, 134.08, 131.79, 129.55, 128.62, 128.25, 128.07, 126.98, 126.81, 126.70, 123.24, 118.73, 105.58, 86.96, 86.85, 59.23, 55.28, 50.41, 23.50; HRMS (ESI, TOF) calcd. for C24H24NO [M+H]+ 342.1858, found 342.1849. 1-(1-Phenyloct-1-yn-3-yl)pyrrolidine (4m): 1H NMR (300 MHz, CDCl3) δ 7.50–7.39 (m, 2H), 7.34–7.27 (m, 3H), 3.68 (dd, J = 8.2, 6.5 Hz, 1H), 2.86–2.61 (m, 4H), 1.97–1.70 (m, 5H), 1.70–0.97 (m, 7H), 0.90 (dd, J = 8.0, 4.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 131.69, 128.17, 127.76, 123.47, 88.30, 85.21, 55.12, 49.73, 35.04, 31.63, 26.40, 23.47, 22.56, 14.06; HRMS (ESI, TOF) calcd. for C18H26N [M+H]+ 256.2065, found 256.2078. 1-(1-Phenyloct-1-yn-3-yl)piperidine (4n): 1H NMR (300 MHz, CDCl3) δ 7.47–7.39 (m, 2H), 7.33–7.26 (m, 3H), 3.48 (dd, J = 9.0, 5.7 Hz, 1H), 2.81–2.62 (m, 2H), 2.55–2.39 (m, 2H), 1.78–1.55 (m, 7H), 1.51–1.39 (m, 3H), 1.38–1.29 (m, 4H), 0.93–0.85 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 131.69, 128.17, 127.71, 123.57, 88.18, 85.58, 58.63, 50.56, 33.43, 31.63, 26.59, 26.18, 24.56, 22.57, 14.06; HRMS (ESI, TOF) calcd. for C19H28N [M+H]+ 270.2222, found 270.2237. 4-(1-Phenyloct-1-yn-3-yl)morpholine (4o): 1H NMR (300 MHz, CDCl3) δ 7.50–7.38 (m, 2H), 7.37–7.23 (m, 3H), 3.85–3.65 (m, 4H), 3.56–3.39 (m, 1H), 2.80–2.67 (m, 2H), 2.62–2.50 (m, 2H), 1.79–1.64 (m, 2H), 1.60–1.42 (m, 2H), 1.37–1.30 (m, 4H), 0.94–0.88 (m, 3H).; 13C NMR (75 MHz, CDCl3) δ 131.61, 128.12, 127.83, 123.15, 87.11, 86.03, 67.06, 58.04, 49.64, 32.83, 31.48, 26.20, 22.49, 13.98; HRMS (ESI, TOF) calcd. for C18H26NO [M+H]+ 272.2014, found 272.2019. 4-(1-Phenyl-3-p-tolylprop-2-ynyl)morpholine (4p): 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 6.9 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.1 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 4.77 (s, 1H), 3.89–3.49 (m, 4H), 2.77–2.50 (m, 4H), 2.35 (s, 3H).; 13C NMR (75 MHz, CDCl3) δ 138.27, 137.88, 131.63, 128.99, 128.54, 128.14, 127.67, 119.84, 88.52, 84.21, 67.13, 62.00, 49.83, 21.43. 4-(1-Phenyl-3-m-tolylprop-2-ynyl)morpholine (4q): 1H NMR (300 MHz, CDCl3) δ 7.75–7.56 (m, 2H), 7.41–7.26 (m, 5H), 7.25–7.17 (m, 1H), 7.16–7.09 (m, 1H), 4.78 (s, 1H), 3.91–3.59 (m, 4H), 2.63 (t, J = 4.6 Hz, 4H), 2.34 (s, 3H) ; 13C NMR (75 MHz, CDCl3) δ 137.95, 137.81, 132.35, 129.08, 128.80, 128.54, 128.16(2C), 127.69, 122.71, 88.63, 84.55, 67.13, 61.97, 49.81, 21.17; HRMS (ESI, TOF) calcd. for C20H22NO [M+H]+ 292.1701, found 292.1703. 4-(1-Phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-ynyl)morpholine(4r): 1H NMR (300 MHz, CDCl3) δ 7.74–7.54 (m, 2H), 7.38 (t, J = 7.1 Hz, 2H), 7.32 (t, J = 7.0 Hz, 1H), 6.73 (s, 2H), 4.78 (s, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.82–3.66 (m, 4H), 2.83–2.41 (m, 4H).; 13C NMR (75 MHz, CDCl3) δ 153.05, 138.81, 137.70, 128.55, 128.24, 127.81, 117.95, 108.96, 88.38, 84.04, 67.12, 62.05, 60.96, 56.19, 49.93; HRMS (ESI, TOF) calcd. for C22H26NO4 [M+H]+ 368.1862, found 368.1863.

4-(3-Morpholino-3-phenylprop-1-ynyl)benzonitrile (4s): 1H NMR (300 MHz, CDCl3) δ 7.65–7.56 (m, 6H), 7.42–7.32 (m, 3H), 4.83 (s, 1H), 3.83–3.64 (m, 4H), 2.63 (t, J = 4.1 Hz, 4H).; 13C NMR (75 MHz, CDCl3) δ 136.85, 132.30, 131.99, 128.43, 128.33, 128.04, 127.72, 118.38, 111.61, 89.90, 86.92, 66.96, 62.00, 49.84; HRMS (ESI, TOF) calcd. for C20H19N2O [M+H]+ 303.1497, found 303.1496. Methyl 4-(3-morpholino-3-phenylprop-1-ynyl)benzoate (4t): 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 7.1 Hz, 2H), 7.34–7.27 (m, 1H), 4.82 (s, 1H), 3.91 (s, 3H), 3.73 (dd, J = 7.8, 3.9 Hz, 4H), 2.64 (t, J = 4.0 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 166.37, 137.18, 131.63, 129.47, 129.39, 128.42, 128.21, 127.83, 127.49, 88.22, 87.71, 66.96, 61.95, 52.13, 49.77.; HRMS (ESI, TOF) calcd. for C21H22NO3 [M+H]+ 336.1600, found 336.1604.